Unravelling the Mysterious Onchocerciasis—Nodding Syndrome Link: New Developments and Future Challenges
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Date
2017
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Annals of Translational Medicine
Abstract
Nodding syndrome (NS) is a chronic, progressive, epileptic encephalopathy of undetermined aetiology, affecting primarily children within the select age group of 5–15 years. Some cases having NS-like clinical features have been described in a number of onchocerciasis-endemic African countries (1), however it is in Northern Uganda (2) and Southern Sudan (3) were epidemic proportions have been noted. First described by Louise Jilek-Aall in Tanzania in the 1960s (4), NS core clinical features are the atonic seizures manifesting as repetitive head nodding episodes (5), often occurring in association with taking a meal or by cold weather, and may be trailed or heralded by other seizure types, behavioural difficulties and deteriorating cognitive function (5-7). In addition, patients may progressively develop other features such as growth decline, delayed sexual development, malnutrition, and psychiatric manifestations such as aggression, catatonia and/or disordered perception (7-9). The consensus case definitions include suspected, probable (further divided in major and minor criteria) and confirmed NS (10).
In 2013 in Uganda, a systematic assessment conducted in three northern districts using the probable case definition, reported approximately 2,000 cases (11). The current total burden in the two geographically distinct areas that have reported epidemics is unknown. However, over the past 15 years, several thousands of children have been affected with a reduction in the number of new cases lately following the introduction of mass treatment with Ivermectin (12) (a microfilaricide that paralyses and kills microfilariae, but does not kill the adult worms).
NS is very destructive to patients and communities because as it evolves, the victims may develop severe physical and functional deficits, making several children drop out of school and become solely dependent on their caregivers, due in part to the poorly controlled epileptic seizures, cognitive impairments and social stigma (13,14). Such a scenario has made NS a key public health problem in Africa, associated with a high burden of morbidity, as well as grave mental, societal and economic challenges to be reckoned with. NS is currently incurable, however symptomatic treatment including anti-epileptic drugs, reassurance, nutritional and physical rehabilitation—may improve the patient’s quality of life (15).
Surprisingly, even after more than half a century following NS first description in the literature, its pathogenesis remains unknown despite previous extensive investigations. Whereas an epidemiological association has consistently been demonstrated between infections with the nematode parasite Onchocerca volvulus (OV), transmitted to humans by the black fly (Simulium sp.) (with a higher sero-positivity prevalence seen among NS cases as well as in those from the affected geographical areas) the evidence regarding its contribution as a cause of NS has been inconclusive (2,5,10). This has stemmed from the lack of proof of microfilariae and adult OV worms’ capacity to invade the central nervous system, in spite of some reports of cerebral spinal fluid (CSF) infestation by microfilariae (16). Over the years, the perplexing relationship between OV infection and NS has continued to baffle scientists and question the role played it plays in the pathophysiology of NS development.
In an attempt to unravel this mystery and provide answers to explain the puzzle of the elusive “OV-NS link”, Nath and his colleagues (17), employed state of the art protein chip methodology, to explore for the presence of potential autoantibodies in pooled sera from patients with nodding syndrome compared to that from unaffected village controls from the same village. They hypothesized that NS may be an autoimmune-mediated disease, and were able to demonstrate ample amounts of autoantibodies to a protein, leiomodin-1 (LMOD1) in patients with NS compared to unaffected controls. LMOD1 autoantibodies were localized to the sera and the CSF of patients with NS and in vitro experiments showed them to be expressed in many neuronal populations. Using a mouse model, they demonstrated LMOD1’s predilection for the CA3 region of the hippocampus, Purkinje cells in the cerebellum and cortical neurons, areas which are coincidentally affected in patients with NS. Interestingly, the investigators in further in vitro experiments also showed that LMOD1 antibodies (Abs) were neurotoxic to cultured human neurons and cross reactive with OV antigens.
These research findings seem to suggest that NS could be an immune mediated, acquired epilepsy syndrome. Over the past decade it has been increasing recognized that autoimmune or inflammatory conditions can cause epilepsy (18-20), and in the literature three Abs have been well portrayed: voltage-gated potassium channels (VGKC), glutamic acid decarboxylase (GAD) and N-methyl-D-aspartate receptor (NMDA) Abs (21). It is estimated that 17.5% of patients with epilepsy suffer from a systemic autoimmune disorder (22).
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Kakooza-Mwesige, A. (2017). Unravelling the mysterious onchocerciasis—nodding syndrome link: new developments and future challenges. Annals of Translational Medicine, 5(24).doi: 10.21037/atm.2017.09.36